Systematic identification and characterization of disease genes for the VATER/VACTERL association

• Applicants: Professorin Dr. Julia Höfele; Professor Dr. Heiko Reutter
• Subject Area: Human Genetics
• Term: from 2015 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274036608

The acronym VATER/VACTERL association refers to the rare, non-random co-occurrence of the following component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Aim of the present research proposal is the identification and characterization of new disease genes for the VATER/VACTERL association. The available patient cohort for human genetic studies comprises samples from 234 unrelated patients with VATER/VACTERL association, 73 patients with VATER/VACTERL-like phenotypes, additional 730 patients with (A), and 418 patients with (TE). Using exome analysis, we previously identified COL2A1, DNAH6, EEF1D, FOXF1, H3F3B, HSPA6, INPP5A, KIAA0556, MEF2C, MTA3, MYH4, PIP5K1C, PLA2G6, SHROOM4, SLC23A1, TRAP1, TRPS1, ZER1, and ZIC3 as VATER/VACTERL candidate genes. We therefore request exome analysis in additional 100 VATER/VACTERL case-parent-trios to identify additional dominant and recessive candidate genes. Large scale re-sequencing analysis of TRAP1 and ZIC3 confirmed both genes as VATER/VACTERL disease genes. Analogous, we intend to re-sequence the remaining 17 candidate genes to confirm some of them as VATER/VACTERL disease genes. For this purpose we will design a “Molecular Inversion Probe (MIP) Assay”. With this cost-effective technique we will re-sequence all 17 candidate genes in a single experiment in the remaining 1.300 patients with VATER/VACTERL association, VATER/VACTERL-like association, ARM, or TE for all of the above mentioned candidate genes. The 100 patients with VATER/VACTERL association that will undergo exome analysis will not be considered for the above mentioned re-sequencing project.The identification of new disease genes for the VATER/VACTERL association may provide new insights into mammalian pattern formation and will lead to a better understanding of molecular mechanisms responsible for the grossly disturbed development of the human vertebral, digestive, cardiac, renal and limb systems. The identification of high-penetrance causative genes will also lead to new diagnostic possibilities.

• DFG Programme: Research Grants